CN1204876C - Oral biological macromolecular medicine administrating system based on biological adhesive microballoon - Google Patents
Oral biological macromolecular medicine administrating system based on biological adhesive microballoon Download PDFInfo
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- CN1204876C CN1204876C CN 02146769 CN02146769A CN1204876C CN 1204876 C CN1204876 C CN 1204876C CN 02146769 CN02146769 CN 02146769 CN 02146769 A CN02146769 A CN 02146769A CN 1204876 C CN1204876 C CN 1204876C
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Abstract
The present invention provides a biodegradable natural polymer polysaccharide bioadhesion microballoon and a preparation method thereof, the therapeutic compositions composed of the microballoon and therapeutic agents, and the carrier of the microballoon when used in the administration system of biological macromolecule medicines. The biodegradable natural polymer polysaccharide bioadhesion microballoon can be prepared with an oil-water two-phase method by the following steps: firstly, dispersing pectin and xanthan gum by an oil phase, and adding chitosan(or the derivatives of chitosan) and polycarbophil; then carrying out crosslinking reaction; finally, separating, washing and drying the microballoon after the crosslinking reaction is completed. The prepared microballoon of the present invention has the advantages of economic preparation process, biodegradability, good biocompatibility and strong bioadhesion performance, and can be used in the administration system of oral biological macromolecule medicines to enhance the bioavailability of the medicines.
Description
Technical field
The present invention relates to a kind of biodegradable natural macromolecule amylose bioadhesive microsphere, the preparation method of this microsphere, the therapeutic combination that this microsphere and biomacromolecule therapeutic agent are formed, and this bioadhesive microsphere is used for the drug delivery system carrier, prepares oral biopharmaceutical macromolecular drug drug-supplying system.
Background technology
The transmission of medicine and delivery system are the key links in the developmental research of new drug.How to guarantee that medicine farthest reaches curative effect shown in the experiment in vitro in vivo, to the toxic and side effects minimum of its hetero-organization of health, nerve, organ, this is a requisite important content in the new drug development process simultaneously.
Along with the develop rapidly of recombinant DNA technology, increasing polypeptide class and protein drug have appearred, increased by 20% as the erythropoietin and the sales volume of interferon medicine for the treatment of the anemia relevant disease in recent years in the whole world.Nearly all now polypeptide and protein drug all are the mode administrations of injection or instillation, so the Application and Development of this class drug delivery system will have huge business potential.In all non-intrusion type route of administration, oral way is the most a kind of beyond doubt, especially among the treatment of chronic disease.Make things convenient for patient to use on the one hand, no pain can also be stopped on the other hand because the infection that injection or instillation cause.
But for biopharmaceutical macromolecular drug, when oral administration, the low ph environment in the gastral cavity and the hydrolysis of the various enzymes in the gastrointestinal tract have caused the reduction even the forfeiture of this class pharmaceutically active; Another principal element is exactly the restriction that the tight structure (intercellular tight connection) of mucomembranous epithelial cell passes through biomacromolecule.Huge obstacle in release when these factors are this class drug oral, transmission and the absorption process.Therefore, how to overcome or avoid the low ph environment in the gastral cavity, the hydrolysis of the various enzymes in the gastrointestinal tract, simultaneously prolong drug the time of staying that absorbs the site to improve drug release and absorbed time, will be the important channel of improving this class bioavailability of medicament.At these factors, researcher has proposed some strategies accordingly, as adopting absorption enhancer, making adhesion tablet to improve at (the Touitou E.J Control Rel 1992 such as holdup time that absorb the site; 21:139.44; Bai JPF.Int J Pharm, 1994; 111:147.52; Wang W.J Drug Target 1996; 4:195.232).According to the literature, adopt a kind of biological adhesive tablet (S.Eiamtrakarn, et al., Biomaterials, 2002 (23) 145-152), during oral release G-CSF (the recombinant human granulocyte colony stimulating growth factor), bioavailability reaches 23%, has reached very ideal effect.But in these methods, some absorption enhancer pair cell has irreversible damage, preparation technology's more complicated of some adhesion tablet, thereby in practical application, have many difficulties.
Bioadhesive drug-supplying system (Bioadhesion Drug Delivery System, BDDS) be meant that adhesiveness polymeric material and body tissue mucomembranous surface produce the tight of long period and contact, make medicine pass through the contact that the contact position mucous epithelium produces the long period, make medicine enter blood circulation, the administering mode of performance part and general action by the contact position mucous epithelium.BDDS generally comprises via position administrations such as oral cavity, nasal cavity, eye, digestive tract, reproductive tract and rectum, and these positions all are covered with mucous layer.But the mucosa secreting mucus, its main component is sticking glycoprotein, glycoprotein, lipoid, inorganic salt, water etc., and sticking glycoprotein can make mucus have glue, cohesion and characteristic such as bonding.The wetting conditions that the body tissue mucomembranous surface is good makes the polymeric material of swellable produce tight contact with it, the molecule segment of adhesion material embed intercellular substance or with mucus in viscosity segment interpenetration, comprehensive functions such as, covalent bond chimeric, electrostatic attraction, Van der Waals force, hydrogen bond, hydrophobic bond by machinery, polymer and mucosa are closely linked, thereby produce the bioadhesion phenomenon, and can keep considerable time.Adhesion intensity is relevant with charge density, molecular weight, Molecular Geometries, swellbility, dissolubility and the concentration of polymeric material.In addition, the pH value of the surface polarity of polymer, segmental compliance, agents area, mucus amount also can produce certain influence.
The similar transdermal administration of mucosa delivery has characteristics such as blood concentration is steady, action period long, easy to use, can play part or general action.And there is not the such horny layer of skin in mucosa, rich blood vessel under the mucosa, and blood flow is rapid, makes mucosa delivery have also that using dosage is little, advantage such as play a role rapidly.
Behind the oral medication, preparation sticks to the gastrointestinal mucosal surface with drug targeting body specific region, by the holdup time of prolong drug in digestive tract, but the action time of prolong drug, in digestive tract or the medicine with specific absorption position can increase it and absorb total amount and absorption rate, improve bioavailability of medicament; Polymer is connected with the absorbing film inner tight, reduce the diffusion path of medicine, increased the overall penetration that is subject to destructive medicine (as polypeptide class and protein-based) at gastrointestinal tract, and can avoid destroying by colon positioning release, also can locate the gastrointestinal disease position, the performance local therapeutic effects.
If particulate delivery system is with the adhesive agent coating or directly to make microparticle formulation then more favourable: modify the surface characteristic that can improve microgranule with adhesive agent, destroy mucociliary clearance mechanism, increase the gastrointestinal tract holdup time; Microgranule closely contacts with mucosa, reduces degraded and the elimination of enzyme to medicine, promotes that granule is ingested.
The key of the slow release/controlled release technology of medicine is to prepare corresponding pharmaceutical carrier.Drug carrier material commonly used mainly is a macromolecular material.As carrier, they must satisfy biodegradable, safety, the requirement of the little grade of toxic and side effects.Studying at present more in the world is some synthetic Biodegradable high molecular polymers, as polyester, polyamino acid, poly-anhydride, poe, Merlon, poly phosphazene etc.Though they can dissolve in vivo, corrosion, product such as organic acid monomers after their degradeds may produce toxic and side effects in vivo.Meanwhile, rise gradually based on the research of the drug carrier material of natural polymers.The safe without toxic side effect of natural polymers, characteristics (as polysaccharide) such as biodegradable just in time meet the requirement of bio-medical material.Simultaneously for the bioadhesive material, in order to guarantee good bioadhesive, polymer must have very strong hydrogen bond action (that is more hydrogen bond form group), enough pliability to penetrate rete malpighii or to organize the slit, be adapted at the surface tension characteristics of mucosal tissue surfaces moistening, in addition, also higher molecular weight need be arranged.
Because biomembranous architectural characteristic, macromole, polar medicine are difficult to pass through biomembrane.Absorption enhancer (see through promoter) just is meant that a class can reversible, special XNOR strengthens the chemical compound of gastrointestinal tract mucous or other tissue adherence permeabilitys of medicine specifically.When absorption enhancer and medicine are taken jointly, will increase the permeability of medicine, and then improve bioavailability of medicament.As drug absorption enhancer must safety non-toxic, can reversibly improve the permeability of medicine.The absorption enhancer of research mainly contains chemical compounds such as bile salt, cyclodextrin derivative, soap and calcium ion chelator at present, but these chemical compounds are because the reason of the interior safety of body has been subjected to certain restriction on dosage when using as drug absorption enhancer.
A large amount of experiments has proved that all chitosan has very strong facilitation to the ability that sees through of medicine transepithelial mucosa cell.It is generally acknowledged that this mechanism of action of chitosan is by its mucoadhesive and result (Artursson, P.et al., the Pharm.Res.1994 (11): 1358-1361 comprehensive to epithelial close-connected regulating action; Dadane, V.et al., Int.J.Pharm., 1999 (182): 21-32).Chitosan be proved to be a kind of safety non-toxic, can be biodegradable, natural macromolecular with biocompatibility.
Polycarbophil (polycarbophil) is a kind of a kind of high molecular polymer that has been applied in pharmaceutic adjuvant, test shows, Polycarbophil also is a kind of mucosa-adherent material, and it can also suppress some protease activities in the intestinal, thereby improves the stability of biopharmaceutical macromolecular drug.(H.L.Lue β en etal., J.Contr.Rel., 45 (1997) 15-23) are so Polycarbophil also is a kind of absorption enhancer preferably.
It is more to utilize natural polymer to prepare the research of controlled release drug delivery system carrier, mainly with alginate, starch and derivant thereof, cellulose and derivant thereof, arabic gum, melon and locust beam gum, hyaluronic acid, chondroitin sulfate, heparin and chitosan etc. are raw material, make microsphere or microcapsule as pharmaceutical carrier, perhaps make the gel that is used for embedding in vivo that contains medicine.(Chen，Jun?et.al.，Carbohydrate?Polymers28(1)1995，69-76；Sinha，V.R.et.al.，International?Journal?ofPharmaceutics?224(1-2)，2001，19-38)。This class controlled release drug system mainly is at small-molecule drug, utilize polysaccharide carrier slowly corrosion in embedding position or the gastrointestinal tract, degraded in vivo, perhaps carrier influences the diffusion coefficient of medicine in carrier to the restriction of drug diffusion, thereby reaches the medicine purpose of sustained release in vivo.Utilize natural macromolecule amylose to prepare the bioadhesive Loaded Microspheres Drug Delivery System, with the bibliographical information that yet there are no of the research that realizes the biomacromolecule oral administration.
Limiting factor during how at the biomacromolecule oral administration takes corresponding strategy to improve this class bioavailability of medicament, will be the significant innovation of biomacromolecule class pharmaceutical dosage form, also will have vast market prospect.
Another object of the present invention provides a kind of method for preparing this natural macromolecule amylose bioadhesive microsphere.
A further object of the present invention provides a kind of therapeutic combination, contains described natural macromolecule amylose bioadhesive microsphere and therapeutic agent.
An also purpose of the present invention provides the application in the oral biopharmaceutical macromolecular drug drug-supplying system of this natural macromolecule amylose bioadhesive microsphere.
The objective of the invention is to realize by following mode:
The natural macromolecule amylose bioadhesive microsphere that the present invention relates to has following characteristic: this microspherulite diameter is between 0.1-3mm, microsphere includes pectin, account for 30%-70% (w/w), xanthan gum accounts for 50%-1% (w/w), Polycarbophil (polycarbophil) accounts for 10-30%, chitosan (or chitosan derivant) accounts for 20-50%, and surplus is a moisture content.Density difference, each composition proportion are also different.
Described natural macromolecule amylose bioadhesive microsphere, preferred pectin accounts for 50%-70% (w/w), and xanthan gum accounts for 15%-5% (w/w), and Polycarbophil (polycarbophil) accounts for 15-20%, chitosan (or chitosan derivant) accounts for 30-40%, and surplus is a moisture content.
Described natural macromolecule amylose bioadhesive microsphere comprises preferably the cross-linking agent of 0.01-5% (w/w), and cross-linking agent can be a kind of or several the share wherein in aldehydes cross-linking agent and the epoxychloropropane.
The preferred glutaraldehyde of aldehydes cross-linking agent, formaldehyde, acetaldehyde and glyceraldehyde.
The method for preparing natural macromolecule amylose bioadhesive microsphere of the present invention comprises the steps:
(1) mixed solution of preparation pectin and xanthan gum: get oil phase and join in the round-bottomed flask and stir, be heated to 30 ℃-90 ℃ simultaneously; Add the water that pectin and xanthan gum are formed, the concentration of pectin solution is 0.5-50% (w/v), and the concentration of xanthan gum solution is 0.1-2% (w/v), and the volume of above-mentioned oil phase is 4-15 times of water; Adding concentration is chitosan (or the chitosan derivant) solution of 0.1-6%; The Polycarbophil solution that adds 1-30%.Temperature remains between 30-90 ℃, stirs after 0.1-1 hour, continues to stir, and finishes after naturally cooling to room temperature;
(2) centrifugalize, usefulness volatility ether organic solvent, deionized water thorough washing product.Promptly get natural macromolecule amylose bioadhesive microsphere behind the low-temperature vacuum drying.
Preferred employing oil phase is mineral oil and vegetable oil, further preferred Oleum Helianthi, Oleum Brassicae campestris, soybean oil, the Semen arachidis hypogaeae wet goods of adopting.
Further preferably can continue to stir 0.1-3 hour in step (1) afterwards, add 1-10% (V/V) (accounting for the water volume) again, concentration is cross-linking agent (aldehydes cross-linking agent and epoxychloropropane friendship Oleum Glycines, the Semen arachidis hypogaeae wet goods of 0.01-2M.
Further preferably can be afterwards in step (1), continue to stir 0.1-3 hour, add 1-10% (V/V) (accounting for the water volume) again, it is crosslinked that concentration is that the cross-linking agent (one or more in aldehydes cross-linking agent and the epoxychloropropane cross-linking agent) of 0.01-2M carries out, and reacts to stop after 0.1-3 hour.With volatile organic solvent, deionized water thorough washing product.The preferred petroleum ether of volatile organic solvent, ether, ethanol and isopropyl alcohol etc.
Aldehydes cross-linking agent in the preferred above-mentioned steps is glutaraldehyde, formaldehyde, acetaldehyde, glyceraldehyde.
Key technology of the present invention has these points: the one, and the selection of natural polymer raw material: pectin is a kind of natural polymers, contains a large amount of carboxyls, hydroxyl in the structure, has the ability of very strong formation hydrogen bond.Xanthan gum is a kind of bacterial polysaccharides, also contains a large amount of carboxyls, oh group.The two all has good bioadhesive.Carboxyl generation chemical action in amino on the chitosan strand and the xanthan gum strand, thus polymeric microspheres stabilize made.Two of key technology is to determine concentration and the two volume ratio each other of xanthan gum solution and pectin solution: because this is the prerequisite of preparation natural macromolecule amylose bioadhesive microsphere.The concentration of the pectin solution of selecting in the preparation method of the present invention is 0.5-50% (w/v).The concentration of xanthan gum solution is 0.1-2% (w/v), and the volume ratio of pectin solution and xanthan gum solution is 1: 0.1-1.Three of key technology is to adopt the profit two phase process, and the method for intensification prepares natural macromolecule amylose bioadhesive microsphere, helps the formation of microsphere like this, and particle size distribution is more even, has improved anti-poly-property.Four of key technology is the mol ratios by the use amount of regulating pectin and xanthan gum, can realize the control to the density of the microsphere of preparation.Five of key technology is temperature controlling in preparation process, temperature is too high during heating, be unfavorable for the stable of biomacromolecule, cross low then can not making and the stretching, extension of xanthan gum macromolecular chain be unfavorable for the formation of the chemical action between pectin, chitosan and Polycarbophil and the xanthan gum.The temperature that adopts among the present invention is 30-90 ℃.Six of key technology is to pass through the processing of steps such as cross-linking reaction in preparation process, and the aldehydes cross-linking agent can form schiff bases with the amido reaction on the chitosan strand; And epoxychloropropane can with hydroxyl generation cross-linking reaction, through after the cross-linking reaction, help improving the intensity of microsphere, thereby improve crushing resistance, and can improve the physicochemical properties of microsphere surface simultaneously or introduce new functional group, help further microsphere being carried out modification.In the present invention, the cross-linking agent use amount seldom and can further be removed residual cross-linking agent by last handling process; In preparation process, do not introduce virose organic solvent or reaction reagent in addition; Moreover pectin, xanthan gum and chitosan are natural polymer and have good biodegradability and biocompatibility, and have been applied to food, pharmaceuticals industry.
A further object of the present invention provides a kind of therapeutic combination, contains described natural macromolecule amylose bioadhesive microsphere and therapeutic agent.Therapeutic agent is meant chemical synthetic drug, biological engineering medicine, and the medicinal active ingredient that extracts from organism.As G-CSF (the recombinant human granulocyte colony stimulating growth factor), theophylline etc.
An also purpose of the present invention provides the application of this natural macromolecule amylose bioadhesive microsphere in oral biopharmaceutical macromolecular drug drug-supplying system.When the preparation medicine carrying microballoons, first the two mixed solution of preparation pectin solution and xanthan gum solution, in mixed solution, add a certain amount of therapeutic agent again and stir, prepare medicine carrying natural macromolecule amylose bioadhesive microsphere according to the method for preparing natural macromolecule amylose bioadhesive microsphere then.With volatile organic solvent, deionized water thorough washing product, promptly get medicine carrying natural polymer microsphere after the drying.
The method of another kind of medicine carrying is that microsphere is immersed in the drug solution, by diffusion, with medicine absorption, be wrapped in microsphere supported in.The amount that is encapsulated in the therapeutic agent in microsphere supported will change with the therapeutic purposes that this medicine reaches.
The last enteric coated capsule of again medicine carrying microballoons that makes being packed into can obtain the biopharmaceutical macromolecular drug of peroral dosage form.Another kind method is carried out enteric coating again with medicine carrying microballoons exactly.The biopharmaceutical macromolecular drug drug-supplying system that makes like this can be avoided the low ph environment in the gastral cavity on the one hand, can utilize its very strong bioadhesive on the other hand, is adsorbed on the intestinal mucosa, prolongs the holdup time, and then improves bioavailability of medicament.
The natural macromolecule amylose bioadhesive microsphere of the present invention's preparation is compared with existing common microsphere drug carrier, and its tangible advantage is: preparation process economy is not high to equipment requirements; The microsphere of preparing has biocompatibility, can biodegradation; Active group is many on the microsphere, is easy to modification, can prepare the microsphere with different surfaces character; The microsphere of preparation has very strong bioadhesive, when carrying out oral administration, can improve bioavailability of medicament; Because microsphere also contains Polycarbophil, chitosan (perhaps chitosan derivant) as drug absorption enhancer, promote transmission, the absorption of biopharmaceutical macromolecular drug, thereby can further improve bioavailability of medicament.
The specific embodiment
Embodiment 1
Get liquid paraffin 150ml, stirring (n=300rpm) heats simultaneously, when temperature rises to 80 ℃, add 10ml15% (w/v) pectin solution and the mutually mixed solution of 10ml1% (w/v) xanthan gum solution, temperature remains between 80-90 ℃, stir after 10 minutes, adding concentration is 2% chitosan (or chitosan derivant) solution 5ml; The Polycarbophil solution 10ml of adding 20%.The room temperature natural cooling continues stirring and stops when temperature drops to room temperature.With petroleum ether, deionized water thorough washing product, promptly get porous natural macromolecule amylose bioadhesive microsphere after 30 ℃ of dryings.Microspherulite diameter is 0.95-1.30mm (＞80%).
Embodiment 2
Get Oleum Helianthi 400ml, stirring (n=400rpm) heats simultaneously, when temperature rises to 40 ℃, add 10ml30% (w/v) pectin solution and the mutually mixed solution of 20ml2% (w/v) xanthan gum solution, temperature remains on about 40 ℃, stir after 20 minutes, adding concentration is 3% chitosan (or chitosan derivant) solution 10ml; The Polycarbophil solution 10ml of adding 10%.Continue to stir the glutaraldehyde that adds 1ml0.025M after 20 minutes.Stop heating, cross-linking reaction stopped after 1.5 hours.With ether, deionized water thorough washing product, after 20 ℃ of dryings, promptly get natural macromolecule amylose bioadhesive microsphere.Microspherulite diameter is 0.86-1.00mm (＞80%).
Embodiment 3
Get Oleum Arachidis hypogaeae semen 300ml, stirring (n=300rpm) heats simultaneously, when temperature rises to 50 ℃, add 10ml 30% (w/v) pectin solution and the mutually mixed solution of 5ml 1.5% (w/v) xanthan gum solution, temperature remains on about 50 ℃, stir after 40 minutes, adding concentration is 4% chitosan (or chitosan derivant) solution 8ml; The Polycarbophil solution 12ml of adding 15%.Continue to stir and stop heating after 20 minutes.With volatile organic solvent (as petroleum ether, ether, ethanol and isopropyl alcohol etc.), deionized water thorough washing product, again with microsphere (pH=10) crosslinked 2 hours in the epoxychloropropane alkaline solution of 0.01M, use volatile organic solvent, deionized water wash then, after 15 ℃ of dryings, obtain crosslinked natural macromolecule amylose bioadhesive microsphere.Microspherulite diameter is 0.98-1.42mm (＞85%).
Embodiment 4
Get Oleum Arachidis hypogaeae semen 200ml, stirring (n=300rpm) heats simultaneously, when temperature rises to 40 ℃, add 10ml25% (w/v) pectin solution and the mutually mixed solution of 20ml2% (w/v) xanthan gum solution, add BSA (bovine serum albumin, simulated albumin matter medicine) 0.015g and stir in mixed solution, temperature remains on about 40 ℃, stir after 20 minutes, adding concentration is 2% chitosan (or chitosan derivant) solution 5ml; The Polycarbophil solution 10ml of adding 20%.Stop heating, continue stirring and when temperature drops to room temperature, stop to stir.With volatile organic solvent, deionized water thorough washing product, promptly get medicine carrying porous natural macromolecule amylose bioadhesive microsphere after the drying.Microspherulite diameter is 0.88-0.98mm (＞80%).
Embodiment 5
Get liquid paraffin 150ml, stirring (n=300rpm) heats simultaneously, when temperature rises to 80 ℃, add 10ml15% (w/v) pectin solution and the mutually mixed solution of 10ml1% (w/v) xanthan gum solution, temperature remains between 80-90 ℃, stir after 10 minutes, adding concentration is 2% chitosan (or chitosan derivant) solution 5ml; The Polycarbophil solution 10ml of adding 20%.The room temperature natural cooling continues stirring and stops when temperature drops to room temperature.With petroleum ether, deionized water thorough washing product, promptly get porous natural macromolecule amylose bioadhesive microsphere after 30 ℃ of dryings.Microspherulite diameter is 0.95-1.30mm (＞80%).The 100mg microsphere is immersed in the BSA solution of 1mg/ml, separated and collected microsphere after 12 hours promptly obtains medicine carrying microballoons.
Claims (9)
1. natural macromolecule amylose bioadhesive microsphere, particle diameter is between 0.1-3mm, and microsphere includes pectin, accounts for 30%-70% (w/w), xanthan gum accounts for 50%-1% (w/w), Polycarbophil (polycarbophil) accounts for 10-30%, and chitosan or chitosan derivant account for 20-50%, and surplus is a moisture content, pectin wherein, xanthan gum, Polycarbophil, the content sum of chitosan and moisture equals 100%.
2. natural macromolecule amylose bioadhesive microsphere according to claim 1 is characterized in that pectin content is 50%-70% (w/w), and xanthan gum content is 15%-5% (w/w).
3. natural macromolecule amylose bioadhesive microsphere according to claim 1 is characterized in that microsphere also includes the cross-linking agent of 0.01-5% (w/w), and this cross-linking agent is wherein a kind of of aldehydes cross-linking agent or epoxychloropropane.
4. natural macromolecule amylose bioadhesive microsphere according to claim 3 is characterized in that the aldehydes cross-linking agent is selected from glutaraldehyde, formaldehyde, acetaldehyde and glyceraldehyde.
5. a method for preparing the described bioadhesive microsphere of claim 1 comprises the steps:
(1) mixed solution of preparation pectin and xanthan gum: get oil phase and join in the round-bottomed flask and stir, be heated to 30 ℃-90 ℃ simultaneously; Add the water that pectin and xanthan gum are formed, the concentration of pectin solution is 0.5-50% (w/v), and the concentration of xanthan gum solution is 0.1-2% (w/v), and the volume of above-mentioned oil phase is 4-15 times of water; Adding concentration is chitosan or the chitosan derivative solution of 0.1-6%; The Polycarbophil solution that adds 1-30%.Temperature remains between 30-90 ℃, stirs after 0.1-1 hour, continues to stir, and finishes after naturally cooling to room temperature;
(2) centrifugalize, usefulness volatility ether organic solvent, deionized water thorough washing product.Promptly get natural macromolecule amylose bioadhesive microsphere behind the low-temperature vacuum drying.
6. method according to claim 5, it is characterized in that step (1) afterwards, also comprise the steps: to continue to stir 0.1-1 hour, add again and account for water volume 1-10%'s (V/V), concentration is that aldehydes or the epoxychloropropane cross-linking agent of 0.01-2M carries out crosslinked, react and stop usefulness volatile organic solvent, deionized water thorough washing product after 0.1-1 hour.
7. method according to claim 6 is characterized in that the aldehydes cross-linking agent is selected from glutaraldehyde, formaldehyde, acetaldehyde and glyceraldehyde.
8. according to claim 5 or 6 described methods, it is characterized in that oil phase is mineral oil or vegetable oil.
9. the application as pharmaceutical carrier drug loading of the described natural macromolecule amylose bioadhesive of claim 1 microsphere in oral biopharmaceutical macromolecular drug administration delivery system.
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